Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper body obesity is the strongest risk factor known for type 2 diabetes mellitus and is a strong risk factor for cardiovascular disease. Obesity is a recognized risk factor for hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia.
Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al., Br. Med. J. 301:835-837 (1990)). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or “Syndrome X” and metabolic syndrome. The worldwide medical cost of obesity and associated disorders is enormous.
Obesity remains a poorly treatable, chronic, essentially intractable metabolic disorder. Accordingly, a need exists for new therapies useful in weight reduction and/or weight maintenance in a subject. Such therapies would lead to a profound beneficial effect on the subject's health.
The present invention provides methods and compositions useful in the control, treatment, and prevention of obesity and obesity-related conditions, disorders, and diseases, such as those referenced above.
The PP-fold family of peptides, Neuropeptide Y (NPY), Peptide YY (PYY), and Pancreatic Polypeptide ((PP) are naturally secreted homologous, 36 amino acid, C-terminally amidated peptides, which are characterized by a common three-dimensional structure—the PP-fold—which is important for the receptor recognition of the peptides.
NPY is a very wide spread Neuropeptide with multiple actions in various parts of both central and peripheral nervous system acting through a number of different receptor subtypes in man such as Y1, Y2, Y4 and Y5.
PP is a hormone, which is released from endocrine cells in the pancreatic islets, almost exclusively governed by vagal cholinergic stimuli elicited especially by food intake. PP has various effects on the gastrointestinal tract, but none of these are observed in isolated cells and organs, and all appear to be dependent on an intact vagal nerve supply. In accordance with this, the PP receptors, which are called Y4 receptors, are located in the brain stem with a strong expression in vagal motor neurons; the activation of which results in the peripheral effects of PP. Additionally, there is a strong expression in the nucleus tractus solitarirus (NTS), the activation of which results in the effects of PP as a satiety hormone.
It should be noted that PP from the brain has access to this area of the brain since the blood brain barrier is leaky in this area where various hormones from the periphery are sensed. Recently it has been surmised that part of the effect of PP on food intake may be mediated through an action on neurons, especially the POMC/CVART neurons in the arcuate nucleus. PP acts through Y4 receptors for which it has a subnanomolar affinity as opposed to PYY and NPY which have nanomolar affinity for this receptor. PP also has an appreciable affinity for the Y5 receptor, but it is not likely of physiological importance in relation to circulating PP due to both lack of access to the cells in the CNS where this receptor is especially expressed and due to the relatively low affinity for PP.
There are four well established types of PP-fold peptide receptors in man, Y1, Y2, Y4 and Y5, which all recognize NPY1-36 and PYY1-36 with similar affinity. Affinity studies suggest that the Y4 receptors bind PP with a subnanomolar affinity corresponding to the concentrations found in plasma whereas NPY and PYY are recognized with much lower affinity.
PP-fold peptides and analogs of these have been suggested for use in the treatment of obesity and associated diseases, including for example, Prader Willi's syndrome, based on the demonstrated effects of certain of these peptides in animal models ands in man and on the fact that obese people have shown low basal levels of PP and PYY as well as lower meal responses of these peptides. It has also been shown since the mid seventies that PP could affect food intake in rodents. In 1993, it was reported that infusion of PP in morbidly obese patients with Prader Willi's syndrome decreased food intake. Recently this finding was confirmed by infusion of PP in normal human subjects where a long lasting suppression of appetite and reduced food intake over 24 hours was observed.
It was suggested in the seventies that PP might be involved in the control of food intake. Recently, evidence from rodent studies has shown that PP is in fact a powerful and efficient anorexigenic peptide when administered peripherally. Since PP has no effect on appetite, food intake, etc., in Y4 knock out animals, it is very likely that PP acts through the Y4 receptor to reduce appetite and food intake. PP has also been shown to have an effect on food intake in diet induced obese animals. Y4 receptors have been found especially in the brain stem in area postreama and on vagal motor neurons where the blood-brain barrier is not efficient and where circulating hormones such as PP can get access to the neurons. Thus, it is likely that the Y4 receptors in the NTS in the brain stem are a major target through which PP acts to suppress appetite and food intake. However, more recent evidence points to the possibility that PP may also act through Y4 receptors in the arcuate nucleus conceivably on the POMC and perhaps also the NPY/AgRP neurons. Low levels of PP are found in obese subjects especially those with Prader-Willi syndrome. High PP levels are found in patients with anorexia nervosa. Importantly, infusion of PP in man decreases appetite and food intake for up to 24 hours. Thus, the effect of PP on food intake was observed after the PP levels in the circulation had returned to normal levels. Infusion of PP has also been shown to decrease food intake in morbidly obese patients with Prader-Willi syndrome.
For the treatment of conditions responsive to Y4 receptor modulation, such as obesity and intestinal hypersecretion, it would be desirable to use PP-fold peptides or peptide mimics such as small molecules which were specific for the Y4 receptor. In particular, it would be highly desirable to use such agents which are selective for the Y4 receptor over the Y1 receptor. This is particularly important since activation of the Y1 receptor is expected to potentially cause unwanted cardiovascular and renal side effects such as vasoconstriction and natriuresis.
Thus, use of selective and efficacious Y4 receptor agonists over Y1 and Y2 receptor agonists would be particularly useful in diseases and conditions susceptible to Y4 receptor activation.
The present invention relates to novel substituted diaminocyclohexane compounds which have the ability to activate, partially activate and/or modulate the NPY Y4 receptor. Such compounds are therefore potentially useful for the treatment or prophylaxis of obesity, to control appetite, feeding, food intake, energy expenditure, caloric intake, gastric motility, diabetes and other related conditions.